The chemical species, 4-hydroxy-α′-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol is generically known as salmeterol.
Salmeterol and its pharmaceutically acceptable salts are long-acting beta-agonists. Salmeterol xinafoate, represented above, is a selective β2-adrenoreceptor agonist. It is clinically used as long-acting inhaled bronchodilator for maintenance treatment of asthma and to control nocturnal asthma. Unlike other bronchodilator drugs, salmeterol is more lipophilic and has many unusual pharmacological properties. The dosage strength is very small (0.021 mg as a metered dose and 0.046 mg as a dry powder inhaler). Due to its very small dosage strength, it is of utmost importance to have the highest possible purity of the API. Also many times the method of particle size reduction is very sensitive to the impurities present and therefore demands highest purity of the API in order to have consistent and desirable results.
There are several processes disclosed in the literature for the synthesis of salmeterol xinafoate, but all of them suffer severe disadvantages with respect to quality, especially on higher scale or on commercial manufacturing scale.
In all the reported synthetic schemes, N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (7a) serves as the key intermediate in the synthesis of salmeterol (GB Patent 2,176,476; U.S. Pat. No. 4,992,474; Tetrahedron Letters, vol. 35(50), pages 9375-9378, 1994; Synthetic Communications, vol. 29(12a), pages 2155-2162, 1999; and Indian Journal of Chemistry, vol. 34B, pages 629-631, 1995).

It is well known in the art that, when salmeterol is synthesised via intermediate (7a), the purity of the drug substance salmeterol is controlled by the purity of intermediate (7a) and to get the desired purity (more than 99.5%) of salmeterol, it is necessary to have the intermediate (7a) of purity of more than 99.5%.
The literature processes do not furnish intermediate (7a) in the required purity, unless methods like high vacuum distillation or purification by column chromatography are resorted to, which are not suitable for commercial manufacturing processes for obvious reasons.
Salmeterol, its salts and solvates are disclosed in GB Patent 2,176,476, which relates to phenethanolamine derivatives, to processes for their preparation, to pharmaceutical compositions comprising them, and to uses of these compounds as medicine.
Processes for the preparation of salmeterol intermediates and related derivatives are disclosed in GB Patent 2,176,476, U.S. Pat. No. 4,992,474 and Tetrahedron Letters, vol. 35(50), pages 9375-9378, 1994.
The present invention discloses a chemical method for purification of intermediate (7a) via formation of an acid salt (8). This method affords intermediate (7a) of very high purity (more than 99.5%).

US 2005/0113608 uses KOH as a base and phase transfer (tetrabutyl ammonium hydrogen sulfate) as a catalyst in toluene as a solvent. The product is isolated after high vacuum distillation.
A preferred embodiment of the present invention uses NaH (sodium hydride) as a base, and Bu4NBr (tetrabutyl ammonium bromide) as a catalyst. In addition to this catalyst the present invention uses NaI (sodium iodide), which helps to minimize side reactions and to get a cleaner product. The product need not be distilled, but can be taken up as such for the preparation of the key intermediate (7a) for salmeterol.
The key intermediate (7a) for salmeterol is disclosed the present application, which teaches a process with novel features viz. purification without vacuum distillation or chromatographic purification, and formation of acid salt (8) in an aqueous organic system.
The process disclosed in GB patent 2,176,476 uses tetrahydrofuran as a solvent with NaH and with catalyst tetrabutyl ammonium hydrogen sulfate. The product is purified by chromatographic purification.
The present inventors have further established that having the intermediate (7a) of highest purity may not be enough to get the desired quality of salmeterol because of the thermal instability of the subsequent intermediates.
Intermediate (9a) is isolated after stripping off the solvent (typically ethyl methyl ketone, acetone, ethyl acetate etc). It was observed that the intermediate (9a) decomposes even when the solvent is stripped off at 30° C. The impurities formed complicate subsequent reactions and inferior quality material is obtained. It is possible to control the decomposition in small-scale laboratory experiments, from which only milligram or a few gram quantities of salmeterol can be obtained. But on a commercial scale the decomposition is unavoidable. In fact, decomposition was observed even at 30° C. over a period of time. Similarly, the next sodium borohydride reduction step gave varied amounts of unknown impurities, which were difficult to separate to the required levels (less than 0.10%).

Thus the processes reported in the prior art suffer the following drawbacks:    (1) Use of either high vacuum distillation or column chromatography purification for N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (7a).
    (2) In the preparation of 2-hydroxy-5-[[[6-(4-phenylbutoxy)hexylbenzyl]amino]acetyl]benzaldehyde (9a), addition of the intermediate (7a) to intermediate (2a) generates impurities which are difficult to remove. In addition to that, after the reaction is over, the reaction mass is extracted in ethyl acetate. This extraction brings many impurities and resinous material with the product, which creates problems for the purification and isolation of the further intermediates. As per the prior art, this intermediate (9a) is isolated by distillation of the solvent, which again generates the impurities/resinous material. These impurities cannot be easily removed by chemical treatment or by conventional ways except column chromatography. Further, intermediate (9a) is thermally less stable and needs to be processed immediately for further steps.
    (3) The quantity of sodium borohydride used in the prior art processes is not sufficient for complete reduction. As sodium borohydride also reacts with methanol, this leaves some partially reduced products and also unreacted intermediate (9a) during the reaction. In order to push these partially reduced intermediates to the intermediate (10a) in the subsequent catalytic hydrogenolysis (N-debenzylation), the reaction needs to be prolonged.
     This leads to generation of impurity G (mentioned in the European Pharmacopoeia 5.2) and other unknown impurities above acceptable limits. These impurities are difficult to remove subsequently.
    (4) In the preparation of 4-hydroxy-α′-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol (11) (i.e. salmeterol), because of the various impurities and resinous material formed in the earlier steps, the isolation of salmeterol (11) is difficult and tricky. Also, the quality varies from batch to batch, as there is very little control over the content of these impurities in the earlier steps.

Because of these limitations the prior art processes are not suitable for scaling up and do not afford quality product.
The present inventors have circumvented the difficulties associated with the earlier processes to obtain salmeterol (11) consistently in very high purity. The process of the present invention is robust and reproducible and can be conveniently employed for commercial production.